PROJECT SUMMARY ? PROJECT 1 Forty to eighty percent of children and preadolescents with autism spectrum disorder (ASD) exhibit clinically significant anxiety symptoms, which are associated with increased social deficits, depression, irritability, and stereotyped and self-injurious behaviors. While it is clear that anxiety symptoms represent a substantial problem for those with ASD, important issues that could inform treatment remain unresolved. For example: 1) there is a lack of clarity about how to differentiate ASD and anxiety symptoms, 2) little is known about how anxiety manifests in those with ASD and intellectual disability (ID), 3) the neural substrates of anxiety in ASD are poorly understood, and 4) it is unclear what treatment(s) to employ to help affected individuals given the early stage of research. In Project 1 of the Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder, we conduct a comparative efficacy trial with neuroimaging in n=132 participants (ages 8-12 years) with ASD and clinically significant anxiety to resolve some of these issues. In Specific Aim 1, we attempt to better characterize the sub-group of children and preadolescents with ASD that exhibit anxiety. We use clinician-administered gold standard measurements as well as parent reports of overlapping constructs such as insistence on sameness, sensory processing issues, and emotion regulation problems that complicate the anxiety phenotype in ASD. We implement multivariate statistical analyses to reveal anxiety sub-types. We then examine whether anxiety prevalence estimates differ depending on whether clinician-administered or common parent questionnaires are used to see if the latter produce lower results for those with ASD and ID. In Specific Aim 2, we conduct a rigorous 16-week randomized, comparative treatment trial of a form of cognitive behavior therapy (CBT) called Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and pill placebo in youth with ASD, IQ>50, and at least one clinically significant anxiety disorder. We compare the relative efficacy of: (1) BIACA vs. pill placebo and sertraline vs. pill placebo in reducing anxiety symptoms, (2) BIACA vs. pill placebo and sertraline vs. pill placebo in reducing the severity of ASD symptoms, and (3) BIACA vs. sertraline in reducing anxiety symptoms across sub-types. We predict that both therapies will be effective, but that BIACA will have advantages in treating ASD symptoms. In Specific Aim 3, we use fMRI to investigate neural predictors of treatment efficacy, markers of treatment-induced change, and signatures of the anxiety sub-types. Here, we hypothesize that reductions in anxiety scores during sertraline and BIACA treatment will be predicted by pre-treatment recruitment of the ventromedial and ventrolateral cortices, along with reduced task-based functional connectivity between these prefrontal regions and the amygdala during the fMRI task. In summary, the goal of Project 1 is to better characterize anxiety in ASD, to rigorously test medication and CBT therapies, and to examine neural mechanisms of anxiety and of treatment change in an effort to make interventions more precise and likely to promote positive outcomes.